Oxy133 Has Anti-adipogenic Effect And Attenuates High-fat Diet-induced Obesity
Akishige Hokugo, DDS, PhD, Luis A. Segovia, MD, Reena Bakshi, MD, Situo Zhou, MD, Kameron Rezzadeh, MD, Patricia Zuk, PhD, Reza Jarrahy, MD.
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
PURPOSE: Obesity is a national health crisis with epidemic proportions, yet effective therapy remains elusive. Novel therapies targeting adipocyte maturation have shown promise in developing treatment alternatives to diet and exercise. To investigate the potential role of oxysterols—naturally occurring byproducts of cholesterol metabolism with antiadipogenic activity--as a clinically viable treatment for obesity, we studied the effects of a specific oxysterol analogue, Oxy133, on the differentiation of adipocytes in vitro and on in vivo adipogenesis in a high-fat diet(HFD)-induced obesity murine model. METHODS: Mouse preadipocyte cells and human adipose-derived stem cells were cultured in adipogenic medium containing DMEM, 10% FBS, penicillin-streptomycin with 0.5mM isobutyl methylxanthine, 50µM indomethacin, 0.5µg/mL dexamethasone, and 10µg/mL insulin. 5µM Oxy133 was added to experimental cultures. In vitro adipocyte activity was assessed by RT-PCR measurement of adipogenic gene expression and Oil-Red-O staining. In vivo effects of oxysterol were assessed by subcutaneous twice weekly subcutaneous injection of Oxy133(10mg/kg) into HFD- mice. RESULTS: Expression of genes associated with adipogenic differentiation was significantly reduced in cells treated with Oxy133 (p<0.05). Oil-Red-O staining was decreased in adipocyte cultures treated with oxysterol. Oxy133 injections significantly reduced weight gain and adipose tissue mass in HFD mice and significantly decreased serum levels of cholesterol and GPT (p<0.05). CONCLUSION: Oxy133 inhibits the differentiation of pre-adipocytes into mature adipocytes and mitigates their function in vitro. Furthermore, Oxy133 appears to attenuate adipogenesis in an in vivo animal model of obesity. These observations warrant further investigation into the potential to use oxysterols in the treament of obesity.
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